Gout Tracked to Genes that Affect Urate Levels

Action Points

Explain to patients that this study suggests that genetic variations that influence levels of uric acid may affect a person's risk of developing gout.

BETHESDA, Md., Sept. 30 -- A genetic risk score based on three genes that influence serum levels of uric acid are associated with a 40-fold increased risk for gout, investigators here reported.

The study confirmed the association of SCL2A9, a urate transporter in the kidney, and identified two other genes thought to be renal urate transporters, Caroline Fox, M.D., of the National Heart, Lung, and Blood Institute, and colleagues reported online in The Lancet.

The 40-fold increased risk of gout associated with the risk score suggests that "knowledge of genotype could help to identify individuals at risk of developing gout long before onset of clinical features of the disease," the authors said.

Aside from predicting risk, the genetic information "could be used to help guide clinical decisions, especially with respect to selection of drugs that are known to increase uric acid concentration and worsen gout," they added.

Hyperuricemia is recognized as a key risk factor for gout and is also a highly heritable trait. Despite that recognition, the mechanisms that determine serum urate levels have not been determined completely, the researchers said.

They had previously demonstrated that the heritability of serum urate concentrations is 63%. That finding suggested that genetic variation might contribute to uric acid concentrations by regulation of uric acid synthesis, excretion, or absorption.

So the authors continued their investigation with a study to identify genetic loci associated with uric acid concentrations.

Single nucleotide polymorphisms (SNPs) associated with urate concentrations were tested for associations with gout.

Data from two large cohort studies provided the basis for the genome-wide association study: 7,699 participants in the Framingham Heart Study and 4,148 from the Rotterdam Study.

The investigators did genome-wide association studies for uric acid, and significant SNPs were replicated in white and black participants in a third study, Atherosclerosis Risk in Communities (ARIC).

SNPs that had genome-wide significant associations with uric acid in the Framingham or Rotterdam study were evaluated for associations with gout.

Three loci in the Framingham cohort (ABCG2 and SLC17A3, in addition to SCL2A9) had genome-wide associations with uric acid, and two of the three demonstrated genome-wide associations in the Dutch cohort.

For each locus, the investigators identified the top SNP.

All three SNPs were direction-consistent for gout in white and black participants in the ARIC study.

An additive genetic risk score at the three loci, derived from the number of high-risk alleles, had graded associations with uric acid and with gout in the Framingham and Rotterdam cohorts and in white participants in the ARIC cohort.

As the number of high-risk alleles increased, so did the prevalence of gout:

2% to 13% in the Framingham cohort

1% to 8% in the Rotterdam cohort

1% to 18% in white participants in ARIC

"At present, prophylaxis for asymptomatic hyperuricemia is not recommended, but our genetic risk score could be used to identify individuals in which asymptomatic hyperuricemia should be treated," the authors said.

"The genes identified in our study could be useful for the ascertainment of novel proteins and molecular mechanisms that affect uric acid concentration, and for novel drug targets to improve treatment of gout," they added.

In an accompanying commentary, Martin Aringer, M.D., and Juergen Graessler, of Carl Gustav University Clinical Center in Dresden, Germany, said that better understanding of the pathophysiologic mechanisms of gout could lead to more effective drugs with fewer side effects.

"Even more exciting is the idea that responding to the defects of these transporter proteins might have further beneficial effects, because they could also transport other molecules besides urate," they said.

The study was funded by the Netherlands Organization for Scientific Research and the National Heart, Lung, and Blood Institute.

Neither the authors nor the editorialists reported conflicts of interest.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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